Corticotropin Releasing Factor, CRF, is a very potent stimulator of the synthesis and secretion of various peptides in the human body. CRF is a 41-residue peptide which constitutes rat/human CRF (r/h CRF), the rat and human species having the same CRF molecule, the structure of which is set forth in U.S. Pat. No. 4,489,163.
Although CRF levels in human peripheral circulation are normally low, there are often elevated levels of CRF in the maternal circulation, which levels progressively increase throughout pregnancy. It has been found that the increasing concentrations of CRF in pathological cases of pregnancy, such as pregnancy-induced hypertension and pre-term labor, were substantially and significantly elevated above those found in normal pregnancies (Campbell et al., J. Clin. Endocr. & Metab., 64:1054-1059, 1987).
It is believed that this maternal plasma CRF most likely originates from the placenta wherein it plays a paracrine role. Placenta cells have been shown to respond to CRF and to produce CRF and its mRNA. Even though CRF concentrations measured in late gestational maternal plasma are similar to levels reported in rat hypothalamic portal blood, which levels are capable of stimulating ACTH release in vitro, it does not appear that there is normally overproduction of ACTH during pregnancy. However, maternal plasma ACTH concentrations do increase slightly with advancing gestation.
There were reports of a protein (hereinafter termed CRF-BP) in human plasma which was capable of biologically inactivating CRF, such as Linton, E.A., et al. Clin. Endo. 28, 315-324 (1988) and Behan, D.P., et al. J. Endo. 122, 23-31 (1989) in the latter of which a partial purification process is disclosed wherein the purity of the isolated protein is estimated to be substantially higher than was later determined. It has been proposed that the role of this protein substance is the prevention of inappropriate pituitary-adrenal stimulation during pregnancy.
This CRF-BP protein is present in such minute amounts in human plasma that it is impractical to commercially extract it; moreover, purification from human plasma to such an extent that the protein could even be used clinically has heretofore not been possible. In addition, the ever-present danger of contamination by a virus, such as HIV, would have rendered any such extracted and purified protein clearly medically unacceptable in the late 1980s and thereafter. Therefore, it was certain that CRF-BP would not be practically available for clinical use unless recombinant DNA production of CRF-BP could be established, which would of course entail knowing the entire amino acid structure of the protein.